A major objective of chronotherapy for indications such as asthma, gastric acid secretion and cardiovascular diseases is to deliver the drug in higher concentrations during the time of greatest need and in lesser concentrations when the need is less. Symptoms associated with xe2x80x9cGERDxe2x80x9d (Gastro Esophageal Reflux Disease) vary in severity throughout a 24-hour period. Accordingly, higher plasma concentrations of a histamine H2 antagonist, such as nizatidine, are required to provide relief from acid secretion in response to fatty meals, as well as to attenuate the xe2x80x9cmidnight gerdxe2x80x9d seen to occur in patients in response to the circadian rhythm to gastric acid secretion, while lower plasma concentrations are adequate in early morning hours and between meals. This is accomplished by administering a pulsatile release dosage form of the present invention, which provides a controlled release of an histamine H2 antagonist from properly designed dosage forms. In particular, the present invention relates to a unit dosage form of an assembly of two or more bead populations, each of which is designed to release the therapeutic agent as a rapid or sustained release pulse after a predetermined delay with resulting plasma concentration varying in a circadian rhythm fashion, thereby enhancing patient compliance and therapeutic efficacy, reducing both cost of treatment and side effects.
Many therapeutic agents are most effective when made available at a constant rate at or near the absorption site. The absorption of therapeutic agents thus made available generally result in desired plasma concentrations leading to maximum efficacy, minimum toxic side effects. Much effort has been devoted to developing sophisticated drug delivery systems, such as osmotic devices, for oral application. However, there are instances where maintaining a constant blood level of a drug is not desirable. For example, a xe2x80x9cposition-controlledxe2x80x9d drug delivery system (e.g., treatment of colon disease or use of colon as an absorption site for peptide and protein based products) may prove to be more efficacious. A pulsatile delivery system is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites. However, there are only a few such orally applicable pulsatile release systems due to the potential limitation of the size or materials used for dosage forms. Ishino et al. disclose a dry-coated tablet form in Chemical Pharm. Bull. Vol. 40 (11), 3036-041 (1992). U.S. Pat. No. 4,851,229 to Magruder et al., U.S. Pat. No. 5,011,692 to Fujioka et al., U.S. Pat. No. 5,017,381 to Maruyama et al., U.S. Pat. No. 5,229,135 to Philippon et al., and U.S. Pat. No. 5,840,329 to Bai disclose preparation of pulsatile release systems. Some other devices are disclosed in U.S. Pat. No. 4,871,549 to Ueda et al. and U.S. Pat. Nos. 5,260,068; 5,260,069; and 5,508,040 to Chen. U.S. Pat. Nos. 5,229,135 and 5,567,441 both to Chen disclose a pulsatile release system consisting of pellets coated with delayed release or water insoluble polymeric membranes incorporating hydrophobic water insoluble agents or enteric polymers to alter membrane permeability. U.S. Pat. No. 5,837,284 to Mehta et al. discloses a dosage form which provides an immediate release dose of methylphenidate upon oral administration, followed by one or more additional doses spread over several hours.
Studies have shown that gastric acid secretion, especially the midnight gerd, follows a circadian rhythm. In such cases, administration of a different kind of unit dosage form which delivers the drug in higher concentrations during the time of greatest need, for example, around dinner and close to midnight, and in lesser concentrations at other times, is needed. Commonly assigned and co-pending U.S. application Ser. No. 09/778,645, which is incorporated in its entirety, discloses a pulsatile release system comprising a combination of two or three pellet populations, each with a well-defined release profile. In accordance with the present invention, a plasma profile is obtained which varies in a circadian rhythm fashion following administration of the novel dosage form.
The present invention provides a pulsatile release, multi-particulate dosage form comprising a mixture of two types of beads comprising a histamine H2 receptor antagonist: IR (Immediate Release) Beads and TPR (Timed Pulsatile Release) Beads. Release profiles which approximate the daily fluctuations in gastric acid secretion are obtainable by blending IR Beads and TPR Beads at an appropriate ratio estimated from pharmaco-kinetic modeling. The IR Beads typically comprise two coatings applied to non-pareil seeds (# 25-30 mesh). The first coating contains a histamine H2 antagonist and a binder, such as hydroxypropyl cellulose. The drug layered beads are coated with a seal coating of Opadry Clear to produce IR Beads. TPR Beads can be produced by applying a second functional membrane comprising a mixture of water insoluble polymer and an enteric polymer to IR Beads, both plasticized polymeric systems being applied from aqueous or solvent based systems.
The pulsatile release oral capsule formulation of the present invention comprises a combination of two types of spherical beads containing the active substance. IR (immediate release) Beads allow immediate release of the active while TPR Beads allow a delayed xe2x80x9cburstxe2x80x9d release (timed pulsatile release) of the active after a lag of 3-4 hours. When administered at bedtime (capsule containing IR Beads+TPR beads), the immediate release of the active is intended to provide relief from acid secretion in response to the meal, while the delayed xe2x80x9cburstxe2x80x9d is intended to attenuate the xe2x80x9cmidnight gerdxe2x80x9d seen to occur in patients in response to the circadian rhythm to gastric acid secretion.